On the in vivo early toxic properties of A-beta 25-35 peptide in the rat hippocampus: involvement of the Receptor-for-Advanced Glycation-End-Products and changes in gene expression.

Amyloid-beta peptide (Aß) deposition is assumed to play a pathogenic role in the brain of Alzheimer's disease patients. To date, the precise mechanisms underlying Aß toxicity are not fully understood. A recent hypothesis suggesting that the Receptor-for-Advanced-Glycation-End-Products (RAGE)-a trans-membrane protein signaling for oxidative stress-is involved in Aß toxicity is gaining attention. Early Aß toxicity could indeed help to explain the deleterious events further produced by this molecule in the brain. In this work, we evaluated the pattern of early expression of RAGE in the toxic model induced by Aß25₋35 in rat CA1 region. Intrahippocampal injections of Aß25₋35 in rats increased the RAGE expression at 24 h post-injection; this event was accompanied by increased components of RAGE downstream signaling in hippocampal cells, such as enhanced expression of the pro-apoptotic factor NF-κB, increased nitric oxide production, LDH leakage, mitochondrial dysfunction, increased TNF-α expression, antioxidant genes down-regulation, and augmented neurodegeneration. Our findings support an active role of RAGE during the early stages of Aß25₋35 toxicity in the hippocampus.

On the early toxic effect of quinolinic acid: involvement of RAGE.

Quinolinic acid (QUIN)-induced toxicity is characterized by N-methyl-d-aspartate receptors over-activation, excitotoxicity and oxidative damage. The characterization of toxic cascades produced by QUIN during the first hours after its striatal infusion is relevant for understanding toxic mechanisms. The role of the receptor-for-advanced-glycation-end-products (RAGE) in the early toxic pattern induced by QUIN was evaluated. RAGE expression - assessed by Western blot analysis and immunofluorescence - was enhanced in the striata of QUIN-lesioned rats at 2h post-lesion. QUIN-induced RAGE up-regulation was accompanied by expression of a RAGE target molecule, nuclear factor kappa B (NF-kappaB), and genes encoding for different enzymes. Other toxic markers linked to RAGE activation were increased by QUIN, including NO formation, premature glial response, lactate dehydrogenase leakage, mitochondrial dysfunction and nuclear condensation. Our results suggest that RAGE up-regulation may play a role in the early stages of QUIN toxicity.